Alzheimer's disease (AD) is an increasingly common and devastating neurodegenerative disease with no available disease-modifying treatments. Most treatment approaches attack a single disease component, either the ?-amyloid or tau protein pathways, for example. However, pleiotropic interventions will likely be needed. The dual-specificity tyrosine phosphorylation-regulated kinase 1A (Dyrk1a) protein represents one such target, with activity in ?-amyloid, tau, and neuroinflammatory pathways. Each of these pathways contributes to neurodegeneration and cognitive deficits in AD. As such, compounds that inhibit Dyrk1a offer a promising new therapeutic approach through novel simultaneous modulation of tau, amyloid, and neuroinflammatory pathways. To this end, our medicinal chemistry efforts have delivered a potent and brain penetrant molecule, Dyr219, which upon dosing in the 3xTg-AD model, improves behavioral and both tau and amyloid neuropathological features of AD with no overt adverse effects (Branca et al., Aging Cell, 2017, 16(5), 1146-1154). In a recent extended 6-month study, we observe no motor effects in wild-type or 3xTg-AD mice following chronic daily dosing, and larger reductions to insoluble, hyperphosphorylated tau, neurofibrillary tangles and insoluble A42 peptides and amyloid plaques. Recently, we have confirmed that Dyr219 also triggers Dyrk1a protein degradation, assigned to inhibition of the Dyrk1a autophosphorylation process. This effect reduces levels of active Dyrk1A in vivo, contributing to efficacy and pointing to a PK-PD relationship between Dyr219 brain exposure and robust neuropathological effects. Ongoing medicinal chemistry efforts directed at enhancement of oral bioavailability and kinome selectivity have recently delivered significantly improved analogs (Dyr476: F% 73%, B/P 0.39) and (DYR533: F% 100%, B/P 0.30 S(35)-selectivity score 0.03). Importantly, Samumed has recently announced the discovery of SM07883, an IND-ready, potent, oral Type 1 Dyrk1a inhibitor which exhibits significant tau pathology reduction in JNPL3 mice. We feel the latter validates the feasibility of our short-term pre-clinical hypothesis and supports the necessity of the aims described herein. In summary, we propose a robust medicinal chemistry pipeline, coupled with in vivo testing of promising compounds in mice, with the aim of delivering molecules superior to Dyr219 that address oral bioavailability, are deemed safe in pre-clinical toxicology models and recapitulate its in vivo effects. We expect our new molecules to be effective at modifying the course of pathology and cognitive decline in AD.